Research Summary

Our basic research program focuses on dysfunction of cortico-limbic-striatal circuits that subserve dysfunctional cognitive control, impulsivity and alterations in reward-related learning with relevance to drug addiction, depression, schizophrenia, and Tourette Syndrome. Our current studies examine how DA/PKA-regulated intracellular signaling and neurotrophin molecules within the prefrontal cortex, amygdala, and accumbens contribute to motivation, learning, and memory processes, including memory reconsolidation. Studies in monkeys have found long-lasting deficits in inhibitory control after repeated cocaine exposure and alterations in reward-related learning. We have recently developed a novel corticosterone model of depression and also examine sex differences in attention, motivation, and impulse control in rodents and underlying molecular alterations. Several addictive/abused drugs such as cocaine, amphetamine, PCP, THC, nicotine, and alcohol are examined using drug self-administration models. We use transgenic mouse models, intracerebral infusion techniques, and viral-vector mediated overexpression of targeted proteins in combination with sophisticated behavioral techniques in mice, rats, and monkeys.

Extensive Research Description

Examples of some major scientific accomplishments: Advanced the Hypothesis of “Frontostriatal Dysfunction in Addiction”. Her work has provided behavioral and biochemical evidence that drug-induced neuroadaptations in cortical and subcortical brain regions result in dysfunctional decision-making abilities and loss of impulse control that, in combination with enhancements of incentive motivation, may contribute to compulsive, habit-driven, behavior in addiction. This theory has received significant attention and has had a major impact on current work in drug addiction research ranging from basic molecular mechanisms, to neurophysiology, and to human neuropsychology and imaging studies. It is, consequently, a major research focus in the field of addiction biology. Her published work in this area has had far reaching impact and includes many “firsts”, for example, showing drug-induced cognitive deficits in orbitofrontal cortex in monkeys as well as in rodent models. Most recently she has extended this work to examine the neurobiology of goal directed actions vs. habitual behavior. This paper was the first to demonstrate a selective modulation of behavior by sex chromosome genes, completely independent of gonadal hormone status. Using a mouse model that segregates sex chromosomes (XX vs. XY) from gonadal phenotype (ovaries vs. testes), she found a sex difference in the rate of habit formation whereby XX mice show faster habit formation compared to XY mice, irrespective of hormonal ‘sex’ status. These data provide new insight into the neurobiological bases of sex differences in the etiology of human habitual or compulsive psychopathologies, such as drug addiction. Together these findings have also had a major influence because Dr. Taylor’s work and emphasis has been on delineating cellular/molecular mechanisms the underlie complex psychological processes. Some examples are listed below.Jentsch, J.D. and Taylor, J.R. (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: Implications for the control over behavior by reward-related stimuli. Psychopharmacology146:373-390.Jentsch, J.D., Olausson, P., De La Garza, II, R., and Taylor, J.R (2002) Impairments of reversal learning and response perseveration after subchronic cocaine administration to monkeys. Neuropsychopharm, 26:183-190Jentsch, J.D., Roth, R.H., and Taylor, J.R. (2000) Impaired performance of an object retrieval/detour task by monkeys after subchronic phencyclidine administration: Evidence for frontostriatal dysfunction. Biological Psychiatry, 48:415-424Hitchcott PK, Quinn JJ, and Taylor JR (2006) Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine, Cerebral Cortex, 17(12):2820-7.Olausson P, Jentsch, J.D., Krueger DD, Tronson NJ, Nairn AC and Taylor, J.R. (2007) Orbitofrontal cortex and cognitive-motivational impairments in psychostimulants addiction: Evidence from impairments in non-human primates. Annals of the New York Academy of Sciences. Aug 14; [Epub ahead of print].Torregrossa MM, Quinn JJ, Taylor JR (2008) Impulsivity, Compulsivity, and Habit: The Role of Orbitofrontal Cortex Revisited. Biological Psychiatry. In pressQuinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Burgoyne PS, and Taylor JR. Chromosomal sex determines habit formation: Relevance to addiction. Nature Neuroscience, 10(11):1398-400

Characterized how dysfunction of dopaminergic/cAMP/PKA signaling in cortico-limbic-striatal circuits underlies drug-induced alterations in reward-related learning and motivation. In addition, demonstrated how sex differences, and estrogen, modify in these behaviors in rodent models of addiction. This elegant work on the effects of drug exposure on appetitive Pavlovian and instrumental conditioning, conditioned reinforcement and motivation has stimulated intense research in the role of learning and memory processes in drug addiction, and how reward-associated memories can influence motivational processes. Several recent reviews by other influential investigators have found this work important and ground-breaking.Taylor, J.R. and Jentsch, J.D. (2001) Repeated Intermittent Administration of Psychomotor Stimulant Drugs Alters the Acquisition of Pavlovian Approach Behavior in Rats: Differential Effects of Cocaine, d-Amphetamine and 3,4-Methylenedioxymethamphetamine (‘Ecstasy’). Biological Psychiatry, 50:137-143Olausson, P., Jentsch, J.D., and Taylor, J.R (2004) Nicotine enhances responding with conditioned reinforcement. Psychopharmacology, 171:173-178Lynch WJ, Kiraly, DD, Caldarone BJ, Picciotto MR, and Taylor JR (2006) Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats. Psychopharmacology 191(2):263-71Olausson, P., Jentsch, J.D., Tronson N., Neve, R.L., Nestler E.J., and Taylor, J.R (2006) ?FosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation, J Neurosci, 26(36):9196-204

Identified that cAMP/PKA/CREB-signaling in amygdala-dependent is involved in appetitive memory consolidation in addition to its well-known role in aversive memory and identified a new role for PKA in memory reconsolidation. Memory reconsolidation was recently “re-discovered”, and is now widely considered to be a process by which previously formed memories can be rendered labile and susceptible to disruption. This may provide a great opportunity for treatments of post-traumatic stress disorder, phobias and several psychiatric conditions. Her recent Nature Neuroscience paper was the first to demonstrate that reconsolidation can be enhanced resulting in increased memory strength. This demonstration has a great impact on our understanding mechanisms of this memory process and, it also opens up a number of new avenues for potential clinical applications utilizing manipulations of reconsolidation in a number of mental disorders including understanding the development and treatment of addiction, as hypothesized in her Nature Neuroscience review.Jentsch, J.D., Olausson, P., Nestler, E.J. and Taylor, J.R (2002) Stimulation of Protein Kinase A Activity in Rat Amygdala enhances Reward-Related Learning Biological Psychiatry, 52:111-118Tronson N.C., Wiseman, S.L., Olausson, P., and Taylor, J.R (2006) Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A. Nature Neurosci 9(2):167-9Tronson N and Taylor JR (2007) Molecular Mechanisms of Memory Reconsolidation. Nature Reviews Neuroscience. 8(4):262-75.

Demonstration that dysfunction of dopaminergic/cAMP/PKA signaling in cortico-limbic-striatal circuits underlies increased impulsivity and alterations in reward-related learning that has relevance to addiction. Evidence and models include cellular, molecular and behavioral analyses in rodents and non-human primates.

Identification of sex differences in cocaine self-administration and other behaviors relevant to addiction and depression.

Development of a novel persistent stress/corticosterone-induced rodent model of depression and characterization of behavioral and cellular/molecular alterations including reversal by chronic anti-depressants.

Role of cAMP/PKA/CREB-signaling in amygdala-dependent memory reconsolidation and learning.

Characterization of prefrontal-cortex striatal interactions in habit learning, and alterations in dopamine function that may contribute to psychiatric disorders associated with compulsive behaviors.

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